Samia Mourah1,2, Baptiste Louveau1,2, Nicolas Dumaz2. 1. Pharmacogenomics Department, Assistance Publique-Hôpitaux de Paris, Hopital Saint Louis. 2. Université de Paris, INSERM UMRS 976, Paris, France.
Abstract
PURPOSE OF REVIEW: Thanks to mitogen-activated protein kinase inhibitors (MAPKi) and immune checkpoint inhibitors (ICI), major progress has been made in the field of melanoma treatment. However, long-term success is still scarce because of the development of resistance. Understanding these mechanisms of resistance and identifying predictive genomic biomarkers are now key points in the therapeutic management of melanoma patients. RECENT FINDINGS: Multiple and complex mechanisms of resistance to MAPKi or ICI have been uncovered in the past few years. The lack of response can be driven by mutations and nonmutational events in tumor cells, as well as by changes in the tumor microenvironment. Melanoma cells are also capable of rapidly switching their molecular and cellular phenotype, leading to an initial drug-tolerant favorizing melanoma resistance. Tumor molecular profiling and circulating tumor cell analyses are of high interest as predictive biomarkers as well as studying immunogenic changes and microbiome in ICI-treated patients. SUMMARY: Resistance to MAPKi and ICI is a key point in therapeutic management of metastatic melanoma patients. Validated biomarkers predicting response to therapy are urgently needed to move toward personalized medicine. Combinatory treatments guided by the understanding of resistance mechanisms will be of major importance in the future of melanoma therapy.
PURPOSE OF REVIEW: Thanks to mitogen-activated protein kinase inhibitors (MAPKi) and immune checkpoint inhibitors (ICI), major progress has been made in the field of melanoma treatment. However, long-term success is still scarce because of the development of resistance. Understanding these mechanisms of resistance and identifying predictive genomic biomarkers are now key points in the therapeutic management of melanomapatients. RECENT FINDINGS: Multiple and complex mechanisms of resistance to MAPKi or ICI have been uncovered in the past few years. The lack of response can be driven by mutations and nonmutational events in tumor cells, as well as by changes in the tumor microenvironment. Melanoma cells are also capable of rapidly switching their molecular and cellular phenotype, leading to an initial drug-tolerant favorizing melanoma resistance. Tumor molecular profiling and circulating tumor cell analyses are of high interest as predictive biomarkers as well as studying immunogenic changes and microbiome in ICI-treated patients. SUMMARY: Resistance to MAPKi and ICI is a key point in therapeutic management of metastatic melanomapatients. Validated biomarkers predicting response to therapy are urgently needed to move toward personalized medicine. Combinatory treatments guided by the understanding of resistance mechanisms will be of major importance in the future of melanoma therapy.
Authors: Lazaro Hiram Betancourt; Jeovanis Gil; Aniel Sanchez; Viktória Doma; Magdalena Kuras; Jimmy Rodriguez Murillo; Erika Velasquez; Uğur Çakır; Yonghyo Kim; Yutaka Sugihara; Indira Pla Parada; Beáta Szeitz; Roger Appelqvist; Elisabet Wieslander; Charlotte Welinder; Natália Pinto de Almeida; Nicole Woldmar; Matilda Marko-Varga; Jonatan Eriksson; Krzysztof Pawłowski; Bo Baldetorp; Christian Ingvar; Håkan Olsson; Lotta Lundgren; Henrik Lindberg; Henriett Oskolas; Boram Lee; Ethan Berge; Marie Sjögren; Carina Eriksson; Dasol Kim; Ho Jeong Kwon; Beatrice Knudsen; Melinda Rezeli; Johan Malm; Runyu Hong; Peter Horvath; A Marcell Szász; József Tímár; Sarolta Kárpáti; Peter Horvatovich; Tasso Miliotis; Toshihide Nishimura; Harubumi Kato; Erik Steinfelder; Madalina Oppermann; Ken Miller; Francesco Florindi; Quimin Zhou; Gilberto B Domont; Luciana Pizzatti; Fábio C S Nogueira; Leticia Szadai; István Balázs Németh; Henrik Ekedahl; David Fenyö; György Marko-Varga Journal: Clin Transl Med Date: 2021-07